Cognitive brain disorders are characterized clinically by progressive loss of memory, cognition, reasoning, executive functioning, planning, judgment and emotional stability, gradually leading to profound mental deterioration.
A wide range of disorders can lead to disturbances of cognition.
Neuropsychological cognitive deficits are common in people with functional neuropsychiatric disorders. Among these, schizophrenia is a chronic, severe and disabling form of psychosis. Scientists have estimated that up to 75% of schizophrenic patients are cognitively impaired. Traditional treatments for schizophrenia are not effective to treat cognitive deficits in schizophrenia, when used at high doses. While it has been reported that more recently developed treatments for schizophrenia, known as “atypical anti-psychotics,” may have some effect on cognitive deficits, the effect may not be lasting or not lead to an improvement in daily functioning. There are currently no drugs approved for the treatment of cognitive deficits in schizophrenia.
More in general across several pathological conditions, with the increase of medical screening for dementia, an increasing number of patients are being identified who do not meet the diagnostic criteria for dementia but nonetheless have significant memory or cognitive impairment, defined as Mild Cognitive Impairment.
Mild Cognitive Impairment (MCI) is a condition characterized by mild recent memory loss without dementia or significant impairment of other cognitive functions to an extent that is beyond that expected for age or educational background. Criteria for diagnosis of MCI are: memory complaint; abnormal activities of daily living; abnormal general cognitive functioning; abnormal memory for age; not demented.
The number of patients falling in the categories of MCI, Age-Associated Memory Impairment, Age-Related Cognitive Decline or similar diagnostic categories is staggering. For example, according to the estimates of Barker et al. Br J Psychiatry, 1995 November; 167(5): 642-8, there are more than 16 million people with Age Associated Memory Impairment in the U.S. alone.
An advisory panel to the US Food and Drug Administration ruled on Mar. 13, 2001, that MCI, “a condition separate from dementia in Alzheimer's Disease (AD),” is a valid target for new drug therapies, regardless of whether a particular drug also slows the progression to dementia. However, so far the drugs that are being used in the treatment of this disease only have mild, temporary effects.
A variety of medications (including nonsteroidal anti-inflammatory drugs) hormones (especially estrogen), vitamins (e.g., vitamin E) and herbal preparations (especially Gingko biloba) have been advocated as treatments for memory loss. Acetylcholinesterase inhibitors, labelled for use in Alzheimer's disease, are also being tested for MCI. While some of these agents hold promise, robust effects from carefully executed, well-controlled clinical trials are still nonexistent. For all these reasons the unmet medical need in MCI is still very high.
Brain disorders characterized by cognition deficits are also those associated with progressive neuronal degeneration, or cell death secondary to trauma, infarction, hypoxia, infection or hydrocephalus and are characterized by memory impairment, but also other cognitive deficits with a pattern that lead to the diagnosis of dementia. Diseases associated with cognitive deficits and dementia are Alzheimer's Disease Parkinson's Disease, Huntington's Disease, HIV, vascular diseases, Pick's or Creutzfeldt-Jacob diseases, multiple sclerosis (MS), Progressive Supranuclear Palsy (PSP), and other white matter disorders. Among these diseases, Alzheimer's Disease represents the fourth most common medical cause of death in the United States. In 2005, Alzheimer's Disease was estimated to affect more than 4 million people in the United States, a number expected to increase within the next 20 years. A large number of drugs have been studied for their effect on improving the cognitive and behavioural aspects of Alzheimer's disease. The FDA has approved five drugs to treat Alzheimer's disease, but at best these drugs only provide mild relief, and do not attack the cause of AD. The five approved drugs for the treatment of AD are: tacrine, donezepil, rivastigmine, galantamine and memantine. Unfortunately these drugs cause only limited and time-depending benefit on cognitive deficits.
Parkinson's Disease (PD) is a chronically, progressive neurological disease, clinically characterized by motor disturbances, including rigidity, bradykinesia, gait disturbances postural instability, and tremor, which generally occurs during rest, but some patients have postural and action tremor components. The neurological hallmarks of PD are degeneration of dopamine neurons in substantia nigra pars compacta, which results in a drastic depletion of dopamine in the striatum, to which these neurons project. Cognitive impairment is also a characteristic of the disease, which occurs even in non-demented and early-stage PD patients and it is not strictly correlated to the motor symptoms of the disease.
It has been clearly recognised that in PD there are deficits related to attention, alertness, perception, motivation, intelligence and finally cognition and memory. These deficits in a large percentage of patients (roughly 50%), in particular in early PD patients, are not extensive and are not severe enough to be classified as dementia. Moreover in a high percentage of these patients the deficits do not progress to dementia. In some individuals cognitive decline can develop in the presence of mild Parkinson disease-related cortical pathology and, conversely, widespread cortical lesions do not necessarily lead to cognitive decline (Braak, H et al, Neurology, 64: 1404-1410, 2005).
At present the most widely used medication in PD is levodopa, which is still considered the golden standard, in spite of the severe motor complications that are evident after long term use of the drug. Since the early 1990s Dopamine Agonists (DA) have gained popularity, both as early therapy to delay the use of levodopa, and as adjunctive therapy to levodopa, when the efficacy of DA alone is not sufficient to control motor impairment of the patients.
Unfortunately, pharmacological intervention aimed at curing Parkinson's induced motor impairment, by restoring dopaminergic tone, not only do not substantially cure cognitive deficits, but very often have negative effects on cognition.
Evidences of no effect on cognition, or even impairment, are reported in the literature with levodopa. This negative findings are described by extensive literature. The following is a non exhaustive list:    Huber S J et al. Neurology, 1987 August; 37(8): 1371-5;    Huber S J et al. Neurology, 1989 March; 39(3): 438-40;    Poewe W et al., Ann Neurol. 1991 June; 29(6): 670-3;    Kulisevsky J et al., Brain, 1996 December; 119 (Pt 6): 2121-32;    Feigin A et al., Brain 2003 Jun. 10; 60(11): 1744).
Also the effects of Dopamine Agonists (DA), a widely prescribed class of compounds for treating PD, on cognition in Parkinson's patients, are often negative.
The effect of pergolide, a mixed D1/D2 agonist, on cognitive functions was evaluated in early-mild Parkinson's Disease (Brusa L et al., J Neural Transm. 2005 February; 112(2): 231-7). Cognitive assessment was performed after the wash-out phase and repeated after eight weeks (end of study) without showing amelioration of cognitive test scores.
In another cohort of mild PD patients pramipexole, a mixed D2/D3 agonist, slightly but significantly worsened verbal fluency, impaired short term verbal memory and attentional-executive functions in comparison to levodopa, although not exceeding normal values. (Brusa L et al., J Neural Transm. 2003, 110: 373-380).
Another dopaminergic drug, apomorphine, had a negative effect on reaction times, without influencing performance accuracy, in visual-spatial working memory (WM) (Costa A et al., Dement Geriatr Cogn Disord. 2003; 15(2): 55-66).
These data suggest that dopaminergic agents and in particular levodopa and dopamine agonists, whereas have proven efficacy in ameliorating motor function in PD patients, have controversial effects on cognition, even worsening some specific tasks.
On the other hand, a sizeable literature supports the hypothesis that cholinergic drugs may improve cognition, in particular in Alzheimer's Disease. More recently Emre M. et al. (New England Journal of Medicine, 2004, 351: 2509-2518) report the first large, multicentre comparison of a cholinesterase inhibitor (rivastigmine) in a double-blind, randomized placebo-controlled trial of patients with PD-related Dementia (PDD). Patients receiving rivastigmine responded better on the two primary outcome measures, Alzheimer's Disease Assessment Scale Cognitive Subscale and Clinical Global Impression of Change, as well as on all secondary outcome measures, including Neuropsychiatric Inventory, activities of daily living, executive functions and MMSE. The differences were moderate, however. More patients in the rivastigmine group (17%) dropped out due to adverse events than in the placebo group (8%), most commonly due to nausea. Even if objective assessment of parkinsonism did not differ between the groups, subjective worsening of tremor was reported more often in the rivastigmine (1.7%) than in the placebo arm, as expected by a drug acting on the cholinergic system. These data suggest that the above described pharmacological intervention can provide some benefit, but this is often obtained at the expenses of severe debilitating side effects, such as worsening in tremors. In fact Parkinson's disease tremor usually improves with anticholinergic medications. Anticholinergics include trihexyphenidyl, benztropine and procyclidine. However, the side effects of anticholinergic therapy, such as dry mouth, blurry vision, urinary difficulty, confusion and negative effects on cognition may limit the use of these agents.
All together these data show that cognitive impairment is still an area of high unmet medical need with no effective drugs. The moderate and inconsistent effect observed with some drugs, e.g. cholinesterase inhibitors, leave space to more effective and safe treatments. In particular in PD, where cholinesterase inhibitors cause worsening of tremors and interventions useful at restoring disease-related motor impairment, such as levodopa or DA, often worsen cognitive functions, the need of new drugs that ameliorate cognition without worsening the motor disturbancies of the disease, is very high.